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Noradrenergic innervation of the dorsal medial prefrontal cortex modulates hypothalamo-pituitary-adrenal responses to acute emotional stress.

ABSTRACT: The medial prefrontal cortex (mPFC) has been proposed to play a role in the inhibition of hypothalamo-pituitary-adrenal (HPA) responses to emotional stress via influences on neuroendocrine effector mechanisms housed in the paraventricular hypothalamic nucleus (PVH). Previous work also suggests an involvement of the locus ceruleus (LC) in behavioral and neuroendocrine responses to a variety of acute stressors. The LC issues a widespread set of noradrenergic projections, and its innervation of the prefrontal cortex plays an important role in the modulation of working memory and attention. Because these operations are likely to be critical for stimulus selection, evaluation, and comparison with past experience in mounting adaptive responses to emotional stress, it follows that the LC-to-mPFC pathway might also be involved in regulating HPA activity under such conditions. Therefore, in the present study, we assessed the effects of selectively ablating noradrenergic inputs into the mPFC, using the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-beta-hydroxylase, on acute restraint stress-induced activation of HPA output. Immunotoxin injections in the dorsal mPFC (centered in the prelimbic cortex) attenuated increments in restraint-induced Fos and corticotropin-releasing factor mRNA expression in the neurosecretory region of PVH, as well as HPA secretory responses. Stress-induced Fos expression in dorsal mPFC was enhanced after noradrenergic deafferentation and was negatively correlated with stress-induced PVH activation, independent of lesion status. These findings identify the LC as an upstream component of a circuitry providing for dorsal mPFC modulation of emotional stress-induced HPA activation.

SUBMITTER: Radley JJ

PROVIDER: S-EPMC2796223 | biostudies-other | 2008 May

REPOSITORIES: biostudies-other

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Noradrenergic innervation of the dorsal medial prefrontal cortex modulates hypothalamo-pituitary-adrenal responses to acute emotional stress.

Radley Jason J JJ Williams Brandon B Sawchenko Paul E PE

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080501 22

The medial prefrontal cortex (mPFC) has been proposed to play a role in the inhibition of hypothalamo-pituitary-adrenal (HPA) responses to emotional stress via influences on neuroendocrine effector mechanisms housed in the paraventricular hypothalamic nucleus (PVH). Previous work also suggests an involvement of the locus ceruleus (LC) in behavioral and neuroendocrine responses to a variety of acute stressors. The LC issues a widespread set of noradrenergic projections, and its innervation of the ...[more]

PMID: 18509042

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Project description:Previous neuroimaging studies have suggested that the experience of flow aligns with a relative increase in activation of the dorsal raphe nucleus (DRN), and relative activation decreases of the medial prefrontal cortex (MPFC) and of the amygdala (AMY). In the present study, Dynamic Causal Modeling (DCM) was used to explore effective connectivity between those brain regions. To test our hypothesis that the DRN causally down-regulates activity of the MPFC and/or of the AMY, 23 healthy male students solved mental arithmetic tasks of varying difficulty during functional magnetic resonance imaging. A "flow" condition, with task demands automatically balanced with participants' skill level, was compared with conditions of "boredom" and "overload". DCM models were constructed modeling full reciprocal endogenous connections between the DRN, the MPFC, the AMY, and the calcarine. The calcarine was included to allow sensory input to enter the system. Experimental conditions were modeled as exerting modulatory effects on various possible connections between the DRN, the MPFC, and the AMY, but not on self-inhibitory connections, yielding a total of 64 alternative DCM models. Model space was partitioned into eight families based on commonalities in the arrangement of the modulatory effects. Random effects Bayesian Model Selection (BMS) was applied to identify a possible winning family (and model). Although BMS revealed a clear winning family, an outstanding winning model could not be identified. Therefore, Bayesian Model Averaging was performed over models within the winning family to obtain representative DCM parameters for subsequent analyses to test our hypothesis. In line with our expectations, Bayesian averaged parameters revealed stronger down-regulatory influence of the DRN on the MPFC when participants experienced flow relative to control conditions. In addition, these condition-dependent modulatory effects significantly predicted participants' experienced degree of flow. The AMY was down-regulated irrespective of condition. The present results suggest a causal role for the DRN in modulating the MPFC, contributing to the experience of flow.

Project description:IntroductionDisulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release.MethodsNoradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors.ResultsFifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats.ConclusionsThis research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.

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Dataset Information

Noradrenergic innervation of the dorsal medial prefrontal cortex modulates hypothalamo-pituitary-adrenal responses to acute emotional stress.

Publications

Noradrenergic innervation of the dorsal medial prefrontal cortex modulates hypothalamo-pituitary-adrenal responses to acute emotional stress.

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